Engineering Biopharmaceuticals

One of the most prominent technical trends of the industry has been the continued increase in the proportion of engineered products coming to the market. The vast majority of biopharmaceuticals approved during the 1980s and early 1990s were either first generation murine monoclonals or unmodified replacement proteins [e.g., human growth hormone (hGH), interferons, blood factor VIII, and erythropoietins—all identical in amino acid sequence to the native human protein and administered in order to replace or augment natural levels of that protein]. This article focuses on more recent approvals and trends in engineering approaches for biopharmaceutical production.

The biopharmaceutical sector continues to grow steadily, with an average of 8–10 new products entering the market each year. By the end of 2006, almost 170 recombinant therapeutic proteins or antibody-based products had gained approval in either the US or the EU, commanding an estimated global market value of $40 billion. One of the most prominent technical trends of the industry has been the continued increase in the proportion of engineered products coming to the market. The vast majority of biopharmaceuticals approved during the 1980s and early 1990s were either first generation murine monoclonals or unmodified replacement proteins [e.g., human growth hormone (hGH), interferons, blood factor VIII, and erythropoietins—all identical in amino acid sequence to the native human protein and administered in order to replace or augment natural levels of that protein].

Advances in protein science and bioinformatics, along with the development of increasingly sensitive and sophisticated analytical methodologies, continue to underscore a greater understanding of the links between protein structure and function. This method allows knowledge-based modification of protein structure to achieve some predefined alteration of functionality.

EARLIER APPROVALS

The focus of many initial engineering experiments entailed alteration of the target protein's native amino acid sequence by molecular techniques, such as site-directed mutagenesis. Some of the alterations included the removal or replacement of large stretches of protein backbone (e.g., chimeric and humanized antibodies); others entailed the addition, removal, or replacement of a single amino acid or, at most, a few amino acids. Examples of the latter approach include several engineered insulin products such as Humalog (insulin lispro, Eli Lilly, Indianapolis, IN).

An alternative engineering approach focuses on the covalent attachment of a chemical moiety to the protein's backbone (e.g., the PEGylation of interferons or the acylation of insulin), or the alteration of natural post-translational modifications that may be present, as in the case of Cerezyme (Genzyme, Cambridge, MA) a recombinant glucocerebrosidase enzyme, whose glycocoponent's sialic acid caps are enzymatically removed to expose mannose residues, promoting macrophage-selective product uptake.

Engineering has been undertaken to achieve various therapeutic objectives, with the most common being:

Table 1. Engineered therapeutic proteins that gained approval in the EU or US (2002–2006 inclusive)

The remainder of this article focuses on more recent approvals and trends in engineering approaches because engineered products approved throughout the 1990s and over the earlier part of this decade have been reviewed elsewhere.1 The 14 engineered products approved since 2002, summarized in Table 1, represent 36% of the 39 new products to come on the market for the first time in either the EU or US in that time period.